Repurposing trypanocidal drugs to tackle amoebic gill disease in Atlantic Salmon

Amoebic gill disease (AGD), caused by Neoparamoeba perurans, is as a major disease in salmonid aquaculture. Treatment options are currently extremely limited. Using an existing state-of the-art drug discovery pipeline at the University of Glasgow, we propose to test the potency of existing licensed and experimental drugs used against the kinetoplastid diseases (Chagas Disease, Sleeping Sickness, Leishmania) for activity against N. perurans in vitro in Scotland prior to in vivo testing of the drug candidates at a unique trial site in Ireland. Crucially N. perurans has an endosymbiotic kinetoplastid (a kinetoplastid living inside every N. perurans cell) on which it relies for essential metabolic processes. Working on the hypothesis that killing the endosymbiont will lead to death of its host, our approach promises to deliver new drugs to address an intractable problem in aquaculture. In doing so it may even drive the costs of these drugs down for medical and veterinary applications in the tropics.

Neoparamoeba perurans causes amoebic gill disease in marine phase Atlantic Salmon and is a major pathogen in salmonid aquaculture, with annual associated losses rapidly approaching those caused by caligid sea lice. N. perurans has a unique cellular biology that can readily exploited given the right tools. Enclosed with in the cytoplasm is an endosymbiotic kinetoplastid called Perkinsela. Genome sequence indicates that the basic physiology of the kinetoplastid endosymbiont contains many of the same biochemical features as those found in other kinetoplastid pathogens of man and domestic livestock (Trypanosoma brucei sp, T. cruzi,. Leishmania sp.), as well as a high level of interdependence between host and symbiont.

Using our existing state-of the-art drug discovery pipeline for kinetoplastids, we propose to test the potency of existing licensed and experimental drugs used against the kinetoplastid diseases for activity against N. perurans in culture, working on the hypothesis that killing the endosymbiont will lead to death of its host. A candidate drug will then be tested for activity against amoebic gill disease in vivo at a marine trial site operated by the Marine Institute, Ireland, both individually as well as in combination and comparison with standard therapies. AGD incidence is positively associated with rising sea surface temperatures. The MI trial site is the most southerly trial site in northern hemisphere and represent a unique opportunity to trial a new treatment for AGD in hyper-endemic setting. Drug residue accumulation in sediment samples at the trial site will be established to assay the potential environmental impact of therapeutant use.

In addition to providing a much-needed new tool for aquaculture, our approach, which aims to repurpose drugs effective against neglected tropical disease but often too expensive to deploy, has the potential drive down their cost by opening new markets for their use.

Salmonid production contributes considerably to the UK economy and food security, constituting around 40% of Scotland's food exports (Scottish Salmon Producers Organization) and is the largest single UK food export in terms of value. Output is predicted to continue to grow both locally and in Norway, Chile and Ireland, with an increase goal of between 30-50% over the next five years. This planned expansion is dependent on maintaining fish welfare and environmental sustainability, which will require that emerging pathologies are addressed effectively.

The principal output of this project will be several candidate drugs for the treatment of AGD, and the field testing of one such candidate.

Ultimately, the impact of any treatment will be measurable in terms of improved survivorship for treated fish that are infected with AGD. As such, the key beneficiary of this research will be the salmonid aquaculture industry, with considerable knock-on benefits to rural economies. The £50,000 in kind contribution from industry is a recognition of this perceived impact. In the UK and Republic of Ireland, salmonid aquaculture supports over 10,000 jobs, many in rural and remote communities, and this project will benefit them. However, given the current value of the salmonid aquaculture industry to the UK exchequer as a high value export commodity, many more people are likely to be indirectly impacted.

Crucially, many of the drugs we propose to repurpose are already in use in a veterinary context in Africa. As such a secondary, developing world, impact may also be felt. Aquaculture market demand for trypanocidal drugs will drive down the cost of these agents, enhancing their availability for medical and veterinary applications in Africa and around the world - potentially impacting millions in terms of improved health and livelihoods.